U.S. patent application number 14/403535 was filed with the patent office on 2015-06-04 for peripheral kappa receptor agonists for reducing pain and inflammation.
This patent application is currently assigned to CARA THERAPEUTICS, INC.. The applicant listed for this patent is CARA THERAPEUTICS, INC.. Invention is credited to Derek T. Chalmers, James B. Jones, Robert H. Spencer.
Application Number | 20150150935 14/403535 |
Document ID | / |
Family ID | 49712832 |
Filed Date | 2015-06-04 |
United States Patent
Application |
20150150935 |
Kind Code |
A1 |
Chalmers; Derek T. ; et
al. |
June 4, 2015 |
PERIPHERAL KAPPA RECEPTOR AGONISTS FOR REDUCING PAIN AND
INFLAMMATION
Abstract
A method of treating of a mammalian subject suffering from an
inflammatory disease or condition by administering a
peripherally-restricted kappa opioid receptor agonist for reducing
the inflammation is provided. The peripherally-restricted kappa
opioid receptor agonist can include a peptide and the peptide can
include D-amino acids. Administration of peripherally-restricted
kappa opioid receptor agonists results in lowering of serum levels
of pro-inflammatory cytokines and elevation of levels of
anti-inflammatory cytokines.
Inventors: |
Chalmers; Derek T.;
(Riverside, CT) ; Jones; James B.; (Metuchen,
NJ) ; Spencer; Robert H.; (New Hope, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CARA THERAPEUTICS, INC. |
Sheldon |
CT |
US |
|
|
Assignee: |
CARA THERAPEUTICS, INC.
Shelton
CT
|
Family ID: |
49712832 |
Appl. No.: |
14/403535 |
Filed: |
June 5, 2013 |
PCT Filed: |
June 5, 2013 |
PCT NO: |
PCT/US2013/044302 |
371 Date: |
November 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61655731 |
Jun 5, 2012 |
|
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Current U.S.
Class: |
514/16.6 ;
514/16.8; 514/18.4; 514/20.8; 514/21.9; 514/282; 514/424 |
Current CPC
Class: |
A61K 31/40 20130101;
A61P 25/00 20180101; A61K 9/0048 20130101; A61K 38/07 20130101;
A61K 31/485 20130101; A61K 9/0019 20130101 |
International
Class: |
A61K 38/07 20060101
A61K038/07; A61K 31/485 20060101 A61K031/485; A61K 9/00 20060101
A61K009/00; A61K 31/40 20060101 A61K031/40 |
Claims
1. A method for reducing kappa opioid receptor-associated
inflammation in a mammalian subject, the method comprising
administering an effective amount of a peripherally-restricted
kappa opioid receptor agonist to the subject.
2. The method according to claim 1, wherein the administering of
the peripherally restricted kappa opioid receptor agonist causes a
reduction in the level of one or more pro-inflammatory cytokines
and/or the increase in an level of one or more anti-inflammatory
cytokines in the blood of the subject.
3. The method according to claim 2, wherein the one or more
pro-inflammatory cytokines are selected from the group consisting
of IL-1.beta., IL-2, IL-4 IL-6, IL-7, IL-8, IL-12, GM-CSF,
TNF.alpha. and IFN.gamma..
4. The method according to claim 2, wherein the one or more
anti-inflammatory cytokines are selected from the group consisting
of IL-5, IL-10 and IL-13.
5. The method according to claim 1, wherein the inflammation is due
to an inflammatory disease or condition.
6. The method according to claim 1, wherein the inflammation is due
to a medical procedure.
7. The method according to claim 1, wherein the inflammation is due
to a physical insult.
8. The method according to claim 5, wherein the inflammatory
disease or condition is selected from the group consisting of
sinusitis, rheumatoid arthritis tenosynovitis, bursitis,
tendonitis, lateral epicondylitis, adhesive capsulitis,
osteomyelitis, osteoarthritic inflammation, inflammatory bowel
disease (IBD), irritable bowel syndrome (IBS), ocular inflammation,
otitic inflammation and autoimmune inflammation.
9. The method according to claim 6, wherein the inflammation is due
to a medical procedure selected from the group consisting of
appendectomy, open colorectal surgery, hernia repair,
prostatectomy, colonic resection, gastrectomy, splenectomy,
colectomy, colostomy, pelvic laparoscopy, tubal ligation,
hysterectomy, vasectomy, cholecystectomy, colonoscopy, cystoscopy,
hysteroscopy, cervical and endometrial biopsy.
10. The method according to claim 6, wherein the inflammation is
due to a physical insult selected from the group consisting of an
abrasion, a cut, a bone fracture, and an open wound.
11. The method according to claim 1, wherein the
peripherally-restricted kappa opioid receptor agonist is
administered by a route of injection selected from the group
consisting of subcutaneous injection, intravenous injection,
intraperitoneal injection, intra-articular injection, intramuscular
injection and intra-ocular injection.
12. The method according to claim 1, wherein the peripherally
restricted kappa opioid receptor agonist comprises a peptide.
13. The method according to claim 2, wherein the peptide comprises
at least four D-amino acids.
14. The method according to claim 1, wherein the peripherally
restricted kappa opioid receptor agonist comprises a synthetic
peptide amide having the formula: ##STR00012## or a stereoisomer,
mixture of stereoisomers, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof; wherein Xaa.sub.1 is selected from the
group consisting of (A)(A')D-Phe, (A)(A')(.alpha.-Me)D-Phe, D-Tyr,
D-Tic, D-tert-leucine, D-neopentylglycine, D-phenylglycine,
D-homophenylalanine, and .beta.-(E)D-Ala, wherein each (A) and each
(A') are phenyl ring substituents independently selected from the
group consisting of --H, --F, --Cl, --NO.sub.2, --CH.sub.3,
--CF.sub.3, --CN, and --CONH.sub.2, and wherein each (E) is
independently selected from the group consisting of cyclobutyl,
cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl; Xaa.sub.2
is selected from the group consisting of (A)(A')D-Phe,
3,4-dichloro-D-Phe, (A)(A')(.alpha.-Me)D-Phe, D-1Nal, D-2Nal,
D-Tyr, (E)D-Ala and D-Trp; Xaa.sub.3 is selected from the group
consisting of D-Nle, D-Phe, (E)D-Ala, D-Leu, (.alpha.-Me)D-Leu,
D-Hle, D-Val, and D-Met; Xaa.sub.4 is selected from the group
consisting of (B).sub.2D-Arg, (B).sub.2D-Nar, (B).sub.2D-Har,
.zeta.-(B)D-Hlys, D-Dap, .epsilon.-(B)D-Lys,
.epsilon.-(B).sub.2-D-Lys, D-Amf, amidino-D-Amf,
.gamma.-(B).sub.2D-Dbu, .delta.-(B).sub.2.alpha.-(B')D-Orn,
D-2-amino-3(4-piperidyl)propionic acid,
D-2-amino-3(2-aminopyrrolidyl)propionic acid,
D-.alpha.-amino-.beta.-amidinopropionic acid,
.alpha.-amino-4-piperidineacetic acid,
cis-.alpha.,4-diaminocyclohexane acetic acid,
trans-.alpha.,4-diaminocyclohexaneacetic acid,
cis-.alpha.-amino-4-methylaminocyclo-hexane acetic acid,
trans-.alpha.-amino-4-methylaminocyclohexane acetic acid,
.alpha.-amino-1-amidino-4-piperidineacetic acid,
cis-.alpha.-amino-4-guanidinocyclohexane acetic acid, and
trans-.alpha.-amino-4-guanidinocyclohexane acetic acid, wherein
each (B) is independently selected from the group consisting of H
and C.sub.1-C.sub.4 alkyl, and (B') is H or (.alpha.-Me); W is
selected from the group consisting of: Null, provided that when W
is null, Y is N; --NH--(CH.sub.2).sub.b-- with b equal to zero, 1,
2, 3, 4, 5, or 6; and --NH--(CH.sub.2).sub.c--O-- with c equal to
2, or 3, provided that Y is C; the moiety ##STR00013## is an
optionally substituted 4 to 8-membered heterocyclic ring moiety
wherein all ring heteroatoms in said ring moiety are N; wherein Y
and Z are each independently C or N; provided that when such ring
moiety is a six, seven or eight-membered ring, Y and Z are
separated by at least two ring atoms; and provided that when such
ring moiety has a single ring heteroatom which is N, then such ring
moiety is non-aromatic; V is C.sub.1-C.sub.6 alkyl, and e is zero
or 1, wherein when e is zero, then V is null and R.sub.1 and
R.sub.2 are directly bonded to the same or different ring atoms;
wherein (i) R.sub.1 is selected from the group consisting of --H,
--OH, halo, --CF.sub.3, --NH.sub.2, --COOH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, amidino, C.sub.1-C.sub.6 alkyl-substituted
amidino, aryl, optionally substituted heterocyclyl, Pro-amide, Pro,
Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, --CN,
--CONH.sub.2, --COR', --SO.sub.2R', --CONR'R'', --NHCOR', OR' and
SO.sub.2NR'R''; wherein said optionally substituted heterocyclyl is
optionally singly or doubly substituted with substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, oxo, --OH, --Cl, --F, --NH.sub.2,
--NO.sub.2, --CN, --COOH, and amidino; wherein R' and R'' are each
independently --H, C.sub.1-C.sub.8 alkyl, aryl, or heterocyclyl or
R' and R'' are combined to form a 4- to 8-membered ring, which ring
is optionally singly or doubly substituted with substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, --C.sub.1-C.sub.6 alkoxy, --OH, --Cl, --F, --NH.sub.2,
--NO.sub.2, --CN, --COOH and amidino; and R.sub.2 is selected from
the group consisting of --H, amidino, singly or doubly
C.sub.1-C.sub.6 alkyl-substituted amidino, --CN, --CONH.sub.2,
--CONR'R'', --NHCOR', --SO.sub.2NR'R'' and --COOH; or (ii) R.sub.1
and R.sub.2 taken together can form an optionally substituted 4- to
9-membered heterocyclic monocyclic or bicyclic ring moiety which is
bonded to a single ring atom of the Y and Z-containing ring moiety;
or (iii) R.sub.1 and R.sub.2 taken together with a single ring atom
of the Y and Z-containing ring moiety can form an optionally
substituted 4- to 8-membered heterocyclic ring moiety to form a
spiro structure; or (iv) R.sub.1 and R.sub.2 taken together with
two or more adjacent ring atoms of the Y and Z-containing ring
moiety can form an optionally substituted 4- to 9-membered
heterocyclic monocyclic or bicyclic ring moiety fused to the Y and
Z-containing ring moiety; wherein each of said optionally
substituted 4-, 5-, 6-, 7-, 8- and 9-membered heterocyclic ring
moieties comprising R.sub.1 and R.sub.2 is optionally singly or
doubly substituted with substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, optionally substituted phenyl, oxo, --OH, --Cl, --F,
--NH.sub.2, --NO.sub.2, --CN, --COOH, and amidino; provided that
when the Y and Z-containing ring moiety is a six or seven membered
ring having a single ring heteroatom and e is zero, then R.sub.1 is
not --OH, and R.sub.1 and R.sub.2 are not both --H; and provided
further that when the Y and Z-containing ring moiety is a six
membered ring having two ring heteroatoms, both Y and Z are N and W
is null, then -(V).sub.eR.sub.1R.sub.2 is attached to a ring atom
other than Z; and if e is zero, then R.sub.1 and R.sub.2 are not
both --H.
15. The method of claim 14, wherein the moiety: ##STR00014## is
selected from the group consisting of: ##STR00015##
##STR00016##
16. The method of claim 14, wherein the synthetic peptide amide has
the structure: ##STR00017##
17. The method of claim 16, wherein the mammalian subject is a
human.
18. The method according to claim 1, wherein the
peripherally-restricted kappa opioid receptor agonist is a
non-narcotic analgesic.
19. The method according to claim 1, wherein the
peripherally-restricted kappa opioid receptor agonist is
asimadoline
(N-[(1S)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-N-methyl-2,2-di-
phenylacetamide).
20. The method according to claim 1, wherein the
peripherally-restricted kappa opioid receptor agonist is
nalfurafine
((2E)-N-[(5.alpha.,6.beta.)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epo-
xymorphinan-6-yl]-3-(3-furyl)-N-methylacrylamide).
Description
RELATED APPLICATION
[0001] The present application claims the benefit of U.S.
provisional patent application Ser. No. 61/655,731 filed Jun. 5,
2012, the disclosure of which is incorporated by reference herein
in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the prevention, inhibition
or treatment of inflammation, especially inflammation resulting
from surgical procedures or other bodily insult. More particularly,
the invention relates to the administration of
peripherally-restricted kappa opioid receptor agonists to reduce
post-surgical inflammation.
RELATED ART
[0003] Non-narcotic analgesics, such as the non-steroidal
anti-inflammatory drugs (NSAIDs) have been used for the management
and treatment of pain and inflammation. However, the NSAIDs (e.g.
ibuprofen) also have unwanted side effects such as hepatotoxicity
and ulcers and gastric bleeding due to Cox1 activity. There is a
need for analgesics and anti-inflammatory agents that are free of
these side effects of NSAIDs.
[0004] Morphine acts at the mu opioid receptor to produce its
analgesic effects. Compounds acting at the kappa opioid receptor
can relieve pain and also suppress inflammation. U.S. Pat. No.
5,965,701 to Junien et al. discloses kappa receptor agonists which
have an affinity for the KOR at least 1,000 times their affinity
for the mu opioid receptor and an ED.sub.50 of not greater than
about 0.5 mg/kg. U.S. Pat. Nos. 7,402,564; 7,727,963 and 7,713,937
disclose synthetic peptide amides that are kappa opioid receptor
ligands and exhibit low P.sub.450 CYP inhibition and low
penetration into the brain. U.S. Pat. No. 7,842,662 discloses
dimeric forms of the synthetic peptide amides that retain their
kappa receptor agonist properties.
[0005] U.S. patent application Ser. No. 12/768,686 discloses the
administration of the kappa opioid agonist synthetic peptide amides
by intravenous, oral and topical routes. US patent application
publication no. 2010/0075910 discloses the use of the kappa opioid
agonist synthetic peptide amides for the treatment of inflammatory
pain.
[0006] The morphine-sparing effects of one such the kappa opioid
agonist synthetic peptide amide, CR845, administered to women after
laparoscopic-assisted hysterectomy has been reported (Menzaghi et
al., 2010 13.sup.th World Congress on Pain). In this reported Phase
2 clinical trial, subjects were administered a 15-minute
intravenous infusion of 0.04 mg/kg CR845 or matching placebo
following recovery from surgery and reaching a pain intensity
baseline level of from 5 to 8 on a scale of zero to 11. Pain
intensity was assessed up to 8 hours after the CR845 infusion or
until morphine was administered by patient controlled analgesia.
Morphine use was reduced by 32% over the first 16 hours
post-infusion in CR845-treated patients versus placebo accompanied
by a significant reduction in opioid side effects (vomiting, nausea
and pruritis, i.e. itching) with no significant changes in clinical
lab test results, vital signs, electrocardiograms, or Ramsey
sedation scale assessment. CR845 was shown to be safe and well
tolerated, and effective in reducing pain intensity when
administered after surgery.
[0007] The link between cytokines and inflammation is well
documented. See for instance: "Cytokines in Disease" Whicher, J. T.
and S. W. Evans (1990) Clin. Chem. 36(7) 1269-1281; "Cytokines and
Inflammation" Ed. E. S. Kimball, (1991) CRC Press, Inc., 2000 Boca
Raton, Fla.; and "Cytokines and Inflammation" Aarons, A. and L.
Borish, (1993) Immuno Methods 3(1) 3-12; and "Role of pro-and
anti-inflammatory cytokines during inflammation: experimental and
clinical findings" C. A. Dinarello J. Biological Regulators and
Homeostatic Agents. (1997) 11: (3) 91-103.
BRIEF DESCRIPTIONS OF THE FIGURES
[0008] FIG. 1 shows the design of the clinical trial described in
Example 1. N: Number of patients; VAS: visual analog pain scale;
PACU: post anesthesia care unit; Opioid Rescue prn: Pro re
nata--Opioid rescue "as needed."
[0009] FIG. 2 shows the relative levels of reduction of
post-operative pain over the first 24 hours after surgery as
demonstrated by the summed pain intensity difference (SPID) over
all time points. Columns are mean values, and the bars are standard
errors about the mean (SEM).
[0010] FIG. 3 shows the relative levels of reduction of
post-operative pain over the first 24 hours after surgery as
demonstrated by the pain intensity difference (PID) from zero to 24
hours.
[0011] FIG. 4 shows the amounts of morphine (in milligrams) self
administered by the patients in each group: placebo-placebo,
placebo-CR845, CR845-placebo, and CR845-CR845 in the intervals: 2-4
hours, 4-12 hours and 12-24 hours post surgery.
[0012] FIG. 5 shows the evaluations of pain relief as assessed by
the patients themselves, demonstrating that pre-treatment with
CR845 was consistently evaluated as very good or excellent by the
highest percentage of patients.
[0013] FIG. 6 shows the results of C-reactive protein assays in
samples of patient serum taken pre surgery and at 1 hour, 8 hours
and 24 hours post laparoscopic hysterectomy after receiving two
placebos or two doses of CR845.
[0014] FIG. 7 shows the results of IL-6 assays in samples of
patient serum taken pre surgery and at 1 hour, 8 hours and 24 hours
post laparoscopic hysterectomy after receiving two placebos or two
doses of CR845.
[0015] FIG. 8A shows the results of TNF.alpha. assays and FIG. 8B
shows the results of IL-1.beta. assays in samples of patient serum
taken at 1 hour, 8 hours and 24 hours post laparoscopic
hysterectomy after receiving two placebos or two doses of
CR845.
[0016] FIG. 9A shows the results of IL-2 assays and FIG. 9B shows
the results of IL-8 assays in samples of patient serum taken at 1
hour, 8 hours and 24 hours post laparoscopic hysterectomy after
receiving two placebos or two doses of CR845. The difference in the
change from baseline level of IL-8 was highly significant
(p=0.007).
[0017] FIG. 10A shows the results of IL-12 assays and FIG. 10B
shows the results of GM-CSF assays in samples of patient serum
taken at 1 hour, 8 hours and 24 hours post laparoscopic
hysterectomy after receiving two placebos or two doses of
CR845.
[0018] FIG. 11A shows the results of IL-6 assays and FIG. 11B shows
the results of IL-7 assays in samples of patient serum taken at 1
hour, 8 hours and 24 hours post laparoscopic hysterectomy after
receiving two placebos or two doses of CR845.
[0019] FIG. 12A shows the results of IL-4 assays and FIG. 12B shows
the results of IFN.gamma. assays from samples of patient serum
taken at 1 hour, 8 hours and 24 hours post laparoscopic
hysterectomy after receiving placebo or a single dose of CR845.
[0020] FIG. 13A shows the results of IL-5 assays and FIG. 13B shows
the results of IL-10 assays in samples of patient serum taken at 1
hour, 8 hours and 24 hours post laparoscopic hysterectomy after
receiving two placebos or two doses of CR845.
[0021] FIG. 14 shows the results of IL-13 assays from samples of
patient serum taken at 1 hour, 8 hours and 24 hours post
laparoscopic hysterectomy after receiving placebo or a single dose
of CR845.
[0022] FIG. 15 shows the incidence of treatment emergent adverse
events (TEAEs) including nausea, vomiting, pruritus and generalized
pruritus through 24 hours after first infusion of CR845 after
laparoscopic hysterectomy in a Phase IIb trial.
SUMMARY
[0023] In one embodiment the present invention provides a method
for reducing kappa opioid receptor-associated inflammation in a
mammalian subject, wherein the method includes administering an
effective amount of a peripherally-restricted kappa opioid receptor
agonist to the subject. In one embodiment the inflammation is due
to an inflammatory disease or condition. In another embodiment the
inflammation is due to a medical procedure.
[0024] In another embodiment the present invention provides a
method for reducing kappa opioid receptor-associated inflammation
in a mammalian subject, the method includes administering an
effective amount of a peripherally-restricted kappa opioid receptor
agonist and wherein the administering of the peripherally
restricted kappa opioid receptor agonist causes a reduction in the
level of one or more pro-inflammatory cytokines and/or the increase
in an level of one or more anti-inflammatory cytokines in the blood
of the subject. In one embodiment the pro-inflammatory cytokines
are chosen from IL-1.beta., IL-2, IL-4 IL-6, IL-7, IL-8,
IL-12(p70), GM-CSF, TNF.alpha. and IFN.gamma.. In another
embodiment the anti-inflammatory cytokines are chosen from IL-5,
IL-10 and IL-13.
[0025] The invention provides the first-in-man use of a
non-narcotic kappa opioid receptor agonist analgesic used as a
pretreatment prior to and/or during surgery to reduce pain and
inflammation. The peripheral restriction of the kappa opioid
receptor agonist analgesics of the invention provides the
non-narcotic analgesic and anti-inflammatory properties due to
action at peripheral kappa receptors and very limited penetration
across the blood brain barrier, and therefore little or no action
at the kappa receptors in the CNS and the brain.
[0026] In another embodiment, the present invention provides a
method for reducing kappa opioid receptor-associated inflammation
in a mammalian subject, the method comprising administering an
effective amount of a peripherally restricted kappa opioid receptor
agonist to the subject and thereby reducing the kappa opioid
receptor-associated inflammation in the mammalian subject.
[0027] The kappa opioid receptor-associated inflammation can be any
inflammatory disease or condition including, but not limited to
sinusitis, rheumatoid arthritis tenosynovitis, bursitis,
tendonitis, lateral epicondylitis, adhesive capsulitis,
osteomyelitis, osteoarthritic inflammation, inflammatory bowel
disease (IBD), irritable bowel syndrome (IBS), ocular inflammation,
otitic inflammation or autoimmune inflammation.
[0028] In one embodiment, the present invention provides a method
for reducing post medical procedure inflammation in a mammalian
subject, the method comprising administering an effective amount of
a peripherally restricted kappa opioid receptor agonist to the
subject prior to the medical procedure that normally causes
post-medical procedure inflammation and thereby reducing the
post-medical procedure inflammation experienced by the subject.
[0029] The subject can be a human patient, a non-human primate or
any other mammal. The non-human primate can be any non-human
primate such as, for instance an ape, gorilla, orangutan, lemur,
monkey or chimpanzee. The non-primate mammal can be the non-primate
mammal such as a pet or companion animal, e.g. a dog or a cat; a
high-value mammal such as a thoroughbred horse, a show animal or a
farm animal, such as a cow, a goat, a sheep or a pig.
[0030] In another embodiment, the invention provides a method for
reducing patient need for morphine, such as for instance as judged
by patient controlled analgesia (PCA) demand.
[0031] In another embodiment, the peripherally restricted kappa
opioid receptor agonist useful in the practice of the present
invention includes a peptide. The peptide can include any amino
acid, such as for instance a natural amino acid, an L-amino acid, a
D-amino acid, or a non-natural amino acid, such as for instance,
and without limitation, D-Ala(cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl), D-Ala (thienyl), D-Nle (i.e., D-norleucine) or
(.alpha.-Me)D-Leu.
[0032] In another embodiment, the peptide includes at least four
D-amino acids. In still another embodiment, the peripherally
restricted kappa opioid receptor agonist includes a synthetic
peptide amide having the formula I:
##STR00001##
or a stereoisomer, mixture of stereoisomers, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof.
[0033] In one embodiment, the residue Xaa.sub.1 can be any of the
following: (A)(A')D-Phe, (A)(A')(.alpha.-Me)D-Phe, D-Tyr, D-Tic,
D-tert-leucine, D-neopentylglycine, D-phenylglycine,
D-homophenylalanine, and .beta.-(E)D-Ala, and wherein each (A) and
each (A') are phenyl ring substituents independently selected from
the group consisting of --H, --F, --Cl, --NO.sub.2, --CH.sub.3,
--CF.sub.3, --CN, and --CONH.sub.2, and wherein each (E) is
independently selected from the group consisting of cyclobutyl,
cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl.
[0034] In another embodiment, the residue Xaa.sub.2 is selected
from the group consisting of (A)(A')D-Phe, 3,4-dichloro-D-Phe,
(A)(A')(.alpha.-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala and
D-Trp.
[0035] In another embodiment, the residue Xaa.sub.3 is selected
from the group consisting of D-Nle, D-Phe, (E)D-Ala, D-Leu,
(.alpha.-Me)D-Leu, D-Hle, D-Val, and D-Met.
[0036] In another embodiment, the residue Xaa.sub.4 is selected
from the group consisting of (B).sub.2D-Arg, (B).sub.2D-Nar,
(B).sub.2D-Har, .zeta.-(B)D-Hlys, D-Dap, .epsilon.-(B)D-Lys,
.epsilon.-(B).sub.2-D-Lys, D-Amf, amidino-D-Amf,
.gamma.-(B).sub.2D-Dbu, .delta.-(B).sub.2.alpha.-(B')D-Orn,
D-2-amino-3(4-piperidyl)propionic acid,
D-2-amino-3(2-aminopyrrolidyl)propionic acid,
D-.alpha.-amino-.beta.-amidinopropionic acid,
.alpha.-amino-4-piperidine-acetic acid,
cis-.alpha.,4-diaminocyclohexane acetic acid,
trans-.alpha.,4-diaminocyclohexaneacetic acid,
cis-.alpha.-amino-4-methylaminocyclo-hexane acetic acid,
trans-.alpha.-amino-4-methylaminocyclohexane acetic acid,
.alpha.-amino-1-amidino-4-piperidineacetic acid,
cis-.alpha.-amino-4-guanidinocyclohexane acetic acid, and
trans-.alpha.-amino-4-guanidinocyclohexane acetic acid, wherein
each (B) is independently selected from --H and C.sub.1-C.sub.4
alkyl, and (B') is H or (.alpha.-Me).
[0037] In another embodiment, the linking group, W is selected from
the group consisting of: Null, provided that when W is null, Y is
N; --NH--(CH.sub.2).sub.b-- with b equal to zero, 1, 2, 3, 4, 5, or
6; and --NH--(CH.sub.2).sub.c--O-- with c equal to 2, or 3,
provided that Y is C.
[0038] In another embodiment, the moiety
##STR00002##
is an optionally substituted 4 to 8-membered heterocyclic ring
moiety wherein all ring heteroatoms in said ring moiety are N;
wherein Y and Z are each independently C or N.
[0039] In another embodiment, the moiety
##STR00003##
is an optionally substituted 4 to 8-membered heterocyclic ring
moiety wherein all ring heteroatoms in said ring moiety are N;
wherein Y and Z are each independently C or N, provided that when
such ring moiety is a six, seven or eight-membered ring, Y and Z
are separated by at least two ring atoms.
[0040] In another embodiment, the moiety
##STR00004##
is an optionally substituted 4 to 8-membered heterocyclic ring
moiety wherein all ring heteroatoms in said ring moiety are N;
wherein Y and Z are each independently C or N provided that when
such ring moiety has a single ring heteroatom which is N, then such
ring moiety is non-aromatic; the group, V is C.sub.1-C.sub.6 alkyl,
and e is zero or 1, wherein when e is zero, then V is null and
R.sub.1 and R.sub.2 are directly bonded to the same or different
ring atoms.
[0041] In another embodiment (i) R.sub.1 is selected from the group
consisting of --H, --OH, halo, --CF.sub.3, --NH.sub.2, --COOH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, amidino,
C.sub.1-C.sub.6 alkyl-substituted amidino, aryl, optionally
substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile,
Lys, Arg, Orn, Ser, Thr, --CN, --CONH.sub.2, --COR', --SO.sub.2R',
--CONR'R'', --NHCOR', OR' and SO.sub.2NR'R''; wherein said
optionally substituted heterocyclyl is optionally singly or doubly
substituted with substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, oxo,
--OH, --Cl, --F, --NH.sub.2, --NO.sub.2, --CN, --COOH, and amidino;
wherein R' and R'' are each independently --H, C.sub.1-C.sub.8
alkyl, aryl, or heterocyclyl or R' and R'' are combined to form a
4- to 8-membered ring, which ring is optionally singly or doubly
substituted with substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy,
--OH, --Cl, --F, --NH.sub.2, --NO.sub.2, --CN, --COOH and amidino;
and R.sub.2 is selected from the group consisting of --H, amidino,
singly or doubly C.sub.1-C.sub.6 alkyl-substituted amidino, --CN,
--CONH.sub.2, --CONR'R'', --NHCOR', --SO.sub.2NR'R'' and --COOH;
or
[0042] (ii) R.sub.1 and R.sub.2 taken together can form an
optionally substituted 4- to 9-membered heterocyclic monocyclic or
bicyclic ring moiety which is bonded to a single ring atom of the Y
and Z-containing ring moiety;
[0043] (iii) R.sub.1 and R.sub.2 taken together with a single ring
atom of the Y and Z-containing ring moiety can form an optionally
substituted 4- to 8-membered heterocyclic ring moiety to form a
spiro structure; or [0044] (iv) R.sub.1 and R.sub.2 taken together
with two or more adjacent ring atoms of the Y and Z-containing ring
moiety can form an optionally substituted 4- to 9-membered
heterocyclic monocyclic or bicyclic ring moiety fused to the Y and
Z-containing ring moiety; wherein each of said optionally
substituted 4-, 5-, 6-, 7-, 8- and 9-membered heterocyclic ring
moieties comprising R.sub.1 and R.sub.2 is optionally singly or
doubly substituted with substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, optionally substituted phenyl, oxo, --OH, --Cl, --F,
--NH.sub.2, --NO.sub.2, --CN, --COOH, and amidino.
[0045] In one embodiment of the invention, the post-medical
procedure inflammation is due to a medical procedure selected from
the following procedures: appendectomy, open colorectal surgery,
hernia repair, prostatectomy, colonic resection, gastrectomy,
splenectomy, colectomy, colostomy, pelvic laparoscopy, tubal
ligation, hysterectomy, vasectomy, cholecystectomy, colonoscopy,
cystoscopy, hysteroscopy, cervical and endometrial biopsy. Other
relevant medical procedures include ocular surgery procedures, such
as for instance, canaloplasty, laser eye surgery and refractive
surgery, such as lasik surgery (laser-assisted in-situ
keratomileusis) and other corneal surgery including corneal
replacement surgery, cataract surgery and retinal surgery. The term
"post-medical procedure" pain and inflammation is used
interchangeably with the term "post-surgical" pain and inflammation
in this specification.
[0046] In still other embodiments the post-medical procedure
inflammation may be due to an orthopedic procedure, such as for
instance knee or shoulder arthroscopy, knee joint and hip joint
replacement, carpel tunnel release, anterior cruciate ligament
reconstruction, repair of femoral neck or ankle fracture,
meniscectomy and laminectomy, to name but a few. Other orthopedic
procedures addressable by the present invention will be immediately
apparent to clinicians, surgeons and those of skill in the art.
DETAILED DESCRIPTION
[0047] The D-isomer of an amino acid is specified by the prefix
"D-" as in "D-Phe" which represents D-phenylalanine, the D-isomer
of phenylalanine. Similarly, the L-isomer is specified by the
prefix "L-" as in "L-Phe." As used herein, D-Arg represents
D-arginine, D-Har represents D-homoarginine, which has a side chain
one methylene group longer than D-Arg, and D-Nar represents
D-norarginine, which has a side chain one methylene group shorter
than D-Arg. Similarly, D-Leu means D-leucine, D-Nle means
D-norleucine, and D-Hle represents D-homoleucine. D-Ala means
D-alanine, D-Tyr means D-tyrosine, D-Trp means D-tryptophan, and
D-Tic means D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid.
D-Val means D-valine and D-Met means D-methionine. D-Pro means
D-proline, Pro-amide means the D- or L-form of proline amide. D-Pro
amide represents D-proline with an amide formed at its carboxy
moiety wherein the amide nitrogen may be alkyl substituted, as in
--NR.sub.aR.sub.b, wherein R.sub.a and R.sub.b are each
independently a C.sub.1-C.sub.6 alkyl group, or one of R.sub.a and
R.sub.b is --H. Gly means glycine, D-Ile means D-isoleucine, D-Ser
means D-serine, and D-Thr means D-threonine. (E)D-Ala means the
D-isomer of alanine which is substituted by the substituent (E) on
the .beta.-carbon. Examples of such substituent (E) groups include
tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
furyl, pyridyl, thienyl, thiazolyl and benzothienyl. Thus,
cyclopentyl-D-Ala means the D-isomer of alanine which is
substituted by cyclopentyl on the .beta.-carbon. Similarly,
D-Ala(2-thienyl) and (2-thienyl)D-Ala are interchangeable and both
mean the D-isomer of alanine substituted at the .beta.-carbon with
thienyl that is attached at the 2-ring position.
[0048] As used herein, D-Nal means the D-isomer of alanine
substituted by naphthyl on the .beta.-carbon. D-2Nal means naphthyl
substituted D-alanine wherein the attachment to naphthalene is at
the 2-position on the ring structure and D-1Nal means
naphthyl-substituted D-alanine wherein the attachment to
naphthalene is at the 1-position on the ring structure. By
(A)(A')D-Phe is meant D-phenylalanine substituted on the phenyl
ring with one or two substituents independently chosen from halo,
nitro, methyl, halomethyl (such as, for example, trifluoromethyl),
perhalomethyl, cyano and carboxamide. By D-(4-F)Phe is meant
D-phenylalanine which is fluoro-substituted in the 4-position of
the phenyl ring. By D-(2-F)Phe is meant D-phenylalanine which is
fluoro-substituted in the 2-position of the phenyl ring. By
D-(4-Cl)Phe is meant D-phenylalanine which is chloro substituted in
the 4-phenyl ring position. By (.alpha.-Me)D-Phe is meant
D-phenylalanine which is methyl substituted at the alpha carbon. By
(.alpha.-Me)D-Leu is meant D-leucine which is methyl substituted at
the alpha carbon.
[0049] The designations (B).sub.2D-Arg, (B).sub.2D-Nar, and
(B).sub.2D-Har represent D-arginine, D-norarginine and
D-homoarginine, respectively, each having two substituent (B)
groups on the side chain. D-Lys means D-lysine and D-Hlys means
D-homolysine. .zeta.-(B)D-Hlys, .epsilon.-(B)D-Lys, and
.epsilon.-(B).sub.2-D-Lys represent D-homolysine and D-lysine each
having the side chain amino group substituted with one or two
substituent (B) groups, as indicated. D-Orn means D-ornithine and
.delta.-(B).alpha.-(B')D-Orn means D-ornithine substituted with
(B') at the alpha carbon and substituted with (B) at the side chain
6-amino group.
[0050] D-Dap means D-2,3-diaminopropionic acid. D-Dbu represents
the D-isomer of alpha, gamma-diamino butyric acid and
(B).sub.2D-Dbu represents alpha, gamma-diamino butyric acid which
is substituted with two substituent (B) groups at the gamma amino
group. Unless otherwise stated, each of the (B) groups of such
doubly substituted residues are independently chosen from H- and
C.sub.1-C.sub.4-alkyl. As used herein, D-Amf means
D-(NH.sub.2CH.sub.2--)Phe, i.e., the D-isomer of phenylalanine
substituted with aminomethyl on its phenyl ring and D-4Amf
represents the particular D-Amf in which the aminomethyl is
attached at the 4-position of the ring. D-Gmf means D-Amf(amidino)
which represents D-Phe wherein the phenyl ring is substituted with
--CH.sub.2NHC(NH)NH.sub.2. Amd represents amidino, --C(NH)NH.sub.2,
and the designations (Amd)D-Amf and D-Amf(Amd) are also
interchangeably used for D-Gmf. The designations Ily and Ior are
respectively used to mean isopropyl Lys and isopropyl Orn, wherein
the side chain amino group is alkylated with an isopropyl
group.
[0051] Alkyl means an alkane radical which can be a straight,
branched, and cyclic alkyl group such as, but not limited to,
methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, t-butyl,
sec-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, cyclohexylethyl.
C.sub.1 to C.sub.8 alkyl refers to alkyl groups having between one
and eight carbon atoms. Similarly, C.sub.1-C.sub.6 alkyl refers to
alkyl groups having between one and six carbon atoms. Likewise,
C.sub.1-C.sub.4 alkyl refers to alkyl groups having between one and
four carbon atoms. By lower alkyl is meant C.sub.1-C.sub.6 alkyl.
Me, Et, Pr, Ipr, Bu, and Pn are interchangeably used to represent
the common alkyl groups: methyl, ethyl, propyl, isopropyl, butyl,
and pentyl, respectively. Although the linkage for an alkyl group
is typically at one end of an alkyl chain, the linkage may be
elsewhere in the chain, e.g. 3-pentyl which may also be referred to
as ethylpropyl, or 1-ethylprop-1-yl. Alkyl-substituted, such as
C.sub.1 to C.sub.6 alkyl-substituted amidino, indicates that the
relevant moiety is substituted with one or more alkyl groups.
[0052] Where a specified moiety is null, the moiety is absent and
if such moiety is indicated to be attached to two other moieties,
such two other moieties are connected by one covalent bond. Where a
connecting moiety is shown herein as attached to a ring at any
position on the ring, and attached to two other moieties, such as
R.sub.1 and R.sub.2, in the case where the connecting moiety is
specified to be null, then the R.sub.1 and R.sub.2 moieties can
each be independently attached to any position on the ring.
[0053] The terms "heterocycle", "heterocyclic ring" and
"heterocyclyl" are used interchangeably herein and refer to a ring
or ring moiety having at least one non-carbon ring atom, also
called a heteroatom, which can be a nitrogen atom, a sulfur atom,
or an oxygen atom. Where a ring is specified as having a certain
number of members, the number defines the number of ring atoms
without reference to any substituents or hydrogen atoms bonded to
the ring atoms. Heterocycles, heterocyclic rings and heterocyclyl
moieties can include multiple heteroatoms independently selected
from nitrogen, sulfur, or oxygen atom in the ring. Rings can be
substituted at any available position. For example, but without
limitation, 6- and 7-membered rings are often substituted in the
4-ring position and 5-membered rings are commonly substituted in
the 3-position, wherein the ring is attached to the peptide amide
chain at the 1-ring position.
[0054] The term "saturated" means an absence of double or triple
bonds and the use of the term in connection with rings describes
rings having no double or triple bonds within the ring, but does
not preclude double or triple bonds from being present in
substituents attached to the ring.
[0055] The term "non-aromatic" in the context of a particular ring
refers to an absence of aromaticity in that ring, but does not
preclude the presence of double bonds within the ring, including
double bonds which are part of an aromatic ring fused to the ring
in question. Nor is a ring atom of a saturated heterocyclic ring
moiety precluded from being double-bonded to a non-ring atom, such
as for instance a ring sulfur atom being double-bonded to an oxygen
atom substituent. As used herein, heterocycles, heterocyclic rings
and heterocyclyl moieties also include saturated, partially
unsaturated and heteroaromatic rings and fused bicyclic ring
structures unless otherwise specified. A heterocycle, heterocyclic
ring or heterocyclyl moiety can be fused to a second ring, which
can be a saturated, partially unsaturated, or aromatic ring, which
ring can be a heterocycle or a carbocycle.
[0056] Where indicated, two substituents can be optionally taken
together to form an additional ring. Rings may be substituted at
any available position. A heterocycle, heterocyclic ring and
heterocyclyl moiety can, where indicted, be optionally substituted
at one or more ring positions with one or more independently
selected substituents, such as for instance, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halo
C.sub.1-C.sub.6 alkyl, optionally substituted phenyl, aryl,
heterocyclyl, oxo, --OH, --Cl, --F, --NH.sub.2, --NO.sub.2, --CN,
--COOH and amidino. Suitable optional substituents of the phenyl
substituent include for instance, but without limitation, one or
more groups selected from C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, halo C.sub.1-C.sub.3 alkyl, oxo, --OH, --Cl, --F,
--NH.sub.2, --NO.sub.2, --CN, --COOH and amidino.
[0057] D-Phe and substituted D-Phe are examples of a suitable amino
acid for residue Xaa.sub.1 in Formula I. The phenyl ring can be
substituted at any of the 2-, 3- and/or 4-positions. Particular
examples of permitted substitutions include, for instance, chlorine
or fluorine at the 2- or 4-positions. Also the alpha-carbon atom
may be methylated. Other equivalent residues which represent
conservative changes to D-Phe can also be used. These include
D-Ala(cyclopentyl), D-Ala(thienyl), D-Tyr and D-Tic. The residue at
the second position, Xaa.sub.2 can also be D-Phe or substituted
D-Phe with such substitutions including a substituent on the
4-position carbon of the phenyl ring, or on both the 3- and
4-positions. Alternatively, Xaa.sub.2 can be D-Trp, D-Tyr or
D-alanine substituted by naphthyl. The third position residue,
Xaa.sub.3 can be any non-polar amino acid residue, such as for
instance, D-Nle, D-Leu, (.alpha.-Me)D-Leu, D-Hle, D-Met or D-Val.
However, D-Ala(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl)
or D-Phe can also be used as Xaa.sub.3. The fourth position residue
Xaa.sub.4 can be any positively charged amino acid residue, such as
for instance, D-Arg and D-Har, which can be optionally substituted
with lower alkyl groups, such as one or two ethyl groups.
Alternatively, D-Nar and any other equivalent residues can be used,
such as, for instance, D-Lys or D-Orn (either of which can be
w-amino group alkylated, for example by methyl or isopropyl groups,
or methylated at the .alpha.-carbon group). Moreover, D-Dbu,
D-4-Amf (which can be optionally substituted with amidino), and
D-Hlys are also suitable amino acids at this position.
[0058] Compounds of the invention contain one or more chiral
centers, each of which has two possible three-dimensional spatial
arrangements (configurations) of the four substituents around the
central carbon atom. These are known as "stereoisomers", and more
specifically as "enantiomers" (all chiral centers inverted) or
"diastereoisomers" (two or more chiral centers, at least one chiral
center remaining the same). In a specific embodiment of the
invention, the amino acids which make up the tetrapeptide backbone,
Xaa.sub.1Xaa.sub.2Xaa.sub.3Xaa.sub.4 are specified to be D-amino
acids i.e., the opposite configuration to those generally found in
mammals.
[0059] References to stereoisomers of the synthetic peptide amides
of the invention in this specification relate to chiral centers
other than the alpha carbons of the D-amino acids which make up
Xaa.sub.1-Xaa.sub.4. Thus, stereoisomers of synthetic peptide
amides that are embodiments of the invention wherein each of
Xaa.sub.1-Xaa.sub.4 are specified to be D-amino acids, do not
include L-amino acids or racemic mixtures of the amino acids at
these positions. Similarly, reference to racemates herein concerns
a center other than the alpha carbons of the D-amino acids which
make up Xaa.sub.1-Xaa.sub.4. Chiral centers in the synthetic
peptide amides of the invention for which a stereoisomer may take
either the R or S configuration include chiral centers in the
moiety attached to the carboxy-terminus of Xaa.sub.4, and also
chiral centers in any amino acid side chain substituents of
Xaa.sub.1-Xaa.sub.4.
[0060] As used herein, "effective amount" or "sufficient amount" of
the peripherally-restricted kappa receptor agonists of the
invention such as the synthetic peptide amides refers to an amount
of the compound as described herein that may be therapeutically
effective to inhibit, prevent, or treat a symptom of a particular
disease, disorder, condition, or side effect. As used herein, a
"reduced dose" of a mu opioid agonist analgesic compound refers to
a dose which when used in combination with a kappa opioid agonist,
such as a synthetic peptide amide of the invention, is lower than
would be ordinarily provided to a particular patient, for the
purpose of reducing one or more side effects of the compound. The
dose reduction can be chosen such that the decrease in the
analgesic or other therapeutic effect of the compound is an
acceptable compromise in view of the reduced side effect(s), where
the decrease in analgesic or other therapeutic effects of the mu
opioid agonist analgesic are wholly or at least partially offset by
the analgesic or other therapeutic effect of the synthetic peptide
amide of other peripherally-restricted kappa receptor agonist of
the invention.
[0061] Co-administration of a mu opioid agonist analgesic compound
with a synthetic peptide amide or other peripherally-restricted
kappa receptor agonist of the invention also permits incorporation
of a reduced dose of the peripherally-restricted kappa receptor
agonist or synthetic peptide amide and/or the mu opioid agonist
analgesic compound to achieve the same therapeutic effect as a
higher dose of the synthetic peptide amide/other
peripherally-restricted kappa receptor agonist or the mu opioid
agonist analgesic compound if administered alone.
[0062] As used herein, "pharmaceutically acceptable" refers to
compounds, materials, compositions, and/or dosage forms which are,
within the scope of sound medical judgment, suitable for contact
with the tissues of human beings and animals without severe
toxicity, irritation, allergic response, or other complications,
commensurate with a benefit-to-risk ratio that is reasonable for
the medical condition being treated.
[0063] As used herein, "dosage unit" refers to a physically
discrete unit suited as unitary dosages for a particular individual
or condition to be treated. Each unit may contain a predetermined
quantity of active synthetic peptide amide or other
peripherally-restricted kappa receptor agonist compound(s)
calculated to produce the desired therapeutic effect(s), optionally
in association with a pharmaceutical carrier. The specification for
the dosage unit forms may be dictated by (a) the unique
characteristics of the active compound or compounds, and the
particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such active compound
or compounds. The dosage unit is often expressed as weight of
compound per unit body weight, for instance, in milligrams of
compound per kilogram of body weight of the subject or patient
(mg/kg). Alternatively, the dosage can be expressed as the amount
of the compound per unit body weight per unit time, (mg/kg/day) in
a particular dosage regimen. In a further alternative, the dosage
can be expressed as the amount of compound per unit body surface
area (mg/m.sup.2) or per unit body surface area per unit time
(mg/m.sup.2/day). For topical formulations, the dosage can be
expressed in a manner that is conventional for that formulation,
e.g., a one-half inch ribbon of ointment applied to the eye, where
the concentration of compound in the formulation is expressed as a
percentage of the formulation.
[0064] As used herein, a "pharmaceutically acceptable salt" refers
to a derivative of a compound wherein the parent compound is
modified by making an acid or a base salt thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic acids
and the like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For instance, such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric acids and the
like; and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic acids, and the like.
[0065] These physiologically acceptable salts are prepared by
methods known in the art, e.g., by dissolving the free amine bases
with an excess of the acid in aqueous alcohol, or neutralizing a
free carboxylic acid with an alkali metal base such as a hydroxide,
or with an amine. Thus, a pharmaceutically acceptable salt of a
synthetic peptide amide or other peripherally-restricted kappa
receptor agonist can be formed from any such peptide amide having
either acidic, basic or both functional groups. For example, a
peptide amide having a carboxylic acid group, may in the presence
of a pharmaceutically suitable base, form a carboxylate anion
paired with a cation such as a sodium or potassium cation.
Similarly, a peptide amide having an amine functional group may, in
the presence of a pharmaceutically suitable acid such as HCl, form
a salt.
[0066] An example of a pharmaceutically acceptable solvate of a
synthetic peptide amide or other peripherally-restricted kappa
receptor agonist is a combination of a synthetic peptide amide or
other peripherally-restricted kappa receptor agonist with solvent
molecules which yields a complex of such solvent molecules in
association with the synthetic peptide amide or other
peripherally-restricted kappa receptor agonist. Combinations of a
drug and propylene glycol (1,2-propanediol) have been used to form
pharmaceutical drug solvates. See for example U.S. Pat. No.
3,970,651. Other suitable solvates are hydrates of drug compounds.
Such hydrates include hydrates which either have comparable
activity or hydrates which are converted back to the active
compound following administration. A pharmaceutically acceptable
N-oxide of a synthetic peptide amide or other
peripherally-restricted kappa receptor agonist is such a compound
that contains an amine group wherein the nitrogen of the amine is
bonded to an oxygen atom.
[0067] A pharmaceutically acceptable crystalline, isomorphic
crystalline or amorphous form of a synthetic peptide amide or other
peripherally-restricted kappa receptor agonist of the invention can
be any crystalline or non-crystalline form of a pharmaceutically
acceptable acidic, basic, zwitterionic, salt, hydrate or any other
suitably stable, physiologically compatible form of the synthetic
peptide amide or other peripherally-restricted kappa receptor
agonist according to the invention.
[0068] The synthetic peptide amides or other
peripherally-restricted kappa receptor agonists of the invention
can be incorporated into pharmaceutical compositions. The
compositions can include an effective amount of the synthetic
peptide amide or other peripherally-restricted kappa receptor
agonist in a pharmaceutically acceptable diluent, excipient or
carrier. Conventional excipients, carriers and/or diluents for use
in pharmaceutical compositions are generally inert and make up the
bulk of the preparation.
[0069] In one embodiment, the present invention provides a method
for reducing post medical procedure pain, post medical procedure
inflammation, or both in a mammalian subject, the method comprising
administering an effective amount of a peripherally restricted
kappa opioid receptor agonist to the subject prior to the medical
procedure that normally causes post-medical procedure pain,
post-medical procedure inflammation, or both and thereby reducing
the post-medical procedure pain and/or the post-medical procedure
inflammation experienced by the subject; wherein the peripherally
restricted kappa opioid receptor agonist has the structure of
formula I:
##STR00005##
wherein the Y and Z-containing ring moiety is a six or seven
membered ring having a single ring heteroatom and e is zero, then
R.sub.1 is not --OH, and R.sub.1 and R.sub.2 are not both --H.
[0070] In another embodiment when the Y and Z-containing ring
moiety of formula I is a six membered ring having two ring
heteroatoms, both Y and Z are N and W is null, then
-(V).sub.eR.sub.1R.sub.2 is attached to a ring atom other than Z;
and when e is zero, then R.sub.1 and R.sub.2 are not both --H.
[0071] In another embodiment of the synthetic peptide useful in the
practice of the present invention, Xaa.sub.1Xaa.sub.2 of formula I
is D-Phe-D-Phe, Xaa.sub.3 is D-Leu or D-Nle and Xaa.sub.4 is
selected from the group consisting of (B).sub.2D-Arg, D-Lys,
(B).sub.2D-Har, .zeta.-(B)D-Hlys, D-Dap, .epsilon.-(B)D-Lys,
.epsilon.-(B).sub.2-D-Lys, D-Amf, amidino-D-Amf,
.gamma.-(B).sub.2D-Dbu and .delta.-(B).sub.2.alpha.-(B')D-Orn.
[0072] In another embodiment of the synthetic peptide of formula I
useful in the practice of the present invention, Xaa.sub.4 is
selected from D-Lys, (B).sub.2D-Har, .epsilon.-(B)D-Lys and
.epsilon.-(B).sub.2-D-Lys.
[0073] In still another embodiment of the synthetic peptide of
formula I useful in the practice of the present invention, W is
null, Y is N and Z is C.
[0074] In another embodiment of the synthetic peptide of formula I,
the Y and Z-containing ring moiety is a six-membered saturated ring
comprising a single ring heteroatom.
[0075] In another embodiment of the synthetic peptide of formula I
useful in the practice of the present invention, the groups R.sub.1
and R.sub.2 taken together with zero, one or two ring atoms of the
Y and Z-containing ring moiety comprise a monocyclic or bicyclic
4-9 membered heterocyclic ring moiety.
[0076] In still another embodiment of the synthetic peptide of
formula I useful in the practice of the present invention, the
moiety e is zero and the groups R.sub.1 and R.sub.2 are each bonded
directly to the same ring atom, R.sub.1 is H, OH, --NH.sub.2,
--COOH, --CH.sub.2COOH, C.sub.1-C.sub.3 alkyl, amidino,
C.sub.1-C.sub.3 alkyl-substituted amidino, dihydroimidazole, D-Pro,
D-Pro amide, or CONH.sub.2 and R.sub.2 is H, --COOH, or
C.sub.1-C.sub.3 alkyl.
[0077] In another embodiment of the synthetic peptide of formula I
useful in the practice of the present invention, the moiety:
##STR00006##
is selected from the following groups:
##STR00007## ##STR00008##
[0078] In another embodiment of the synthetic peptide of formula I
useful in the practice of the present invention, Xaa.sub.1Xaa.sub.2
is D-Phe-D-Phe, Xaa.sub.3 is D-Leu or D-Nle and Xaa.sub.4 is
selected from (B).sub.2D-Arg, D-Lys, (B).sub.2D-Har,
.zeta.-(B)D-Hlys, D-Dap, .epsilon.-(B)D-Lys,
.epsilon.-(B).sub.2-D-Lys, D-Amf, amidino-D-Amf,
.gamma.-(B).sub.2D-Dbu and .delta.-(B).sub.2.alpha.-(B')D-Orn.
[0079] In another embodiment of the synthetic peptide useful in the
practice of the present invention is CR845 having the structure:
D-Phe-D-Phe-D-Leu-D-Lys-[.omega.(4-aminopiperidine-4-carboxylic
acid)]-OH:
##STR00009##
[0080] Asimadoline, a selective, non-peptidic kappa-opioid receptor
agonists is also useful I methods according to the present
invention for pretreatment prior to surgery in order to reduce
post-surgical pain and inflammation. Asimadoline has the
diarylacetamide structure shown below:
##STR00010## [0081]
(N-[(1S)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-N-methyl-2,2-di-
phenylacetamide).
[0082] Nalfurafine (also known as AC-820, TRK-820) is a kappa
opioid receptor agonist marketed as a treatment for uremic pruritus
in hemodialysis patients. Nalfurafine is another kappa opioid
receptor agonist useful according to the present invention for
pretreatment prior to surgery in order to reduce post-surgical pain
and inflammation.
[0083] Nalfurafine is
(2E)-N-[(5.alpha.,6.beta.)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epox-
ymorphinan-6-yl]-3-(3-furyl)-N-methylacrylamide, and has the
following chemical structure:
##STR00011##
[0084] In one embodiment of the invention, the method further
includes administering another dose of the peripherally restricted
kappa opioid receptor agonist to the subject during or after the
medical procedure.
[0085] In another embodiment of the method of the invention, the
relief from post-medical procedure pain is such that the subject
self administers little or no patient controlled analgesia (PCA)
after surgery and/or during recovery.
[0086] In another embodiment of the method of the invention, the
relief from post-medical procedure inflammation is accompanied by
relief from pruritis during the period of recovery from the medical
procedure.
[0087] In one embodiment of the invention, the peripherally
restricted kappa opioid receptor agonist useful in the practice of
the present invention is a non-narcotic analgesic.
[0088] In another embodiment of the method of the invention, the
peripherally restricted kappa opioid receptor agonist is
administered by a route of injection selected from the group
consisting of subcutaneous injection, intravenous injection,
intraperitoneal injection, intra-articular injection, intramuscular
injection or intra-ocular injection.
[0089] Inflammation is a complex biological response of vascular
tissues to harmful stimuli, such as pathogens, damaged cells, or
irritants. Inflammation can be acute or chronic, and is often
characterized by fever in mammals. Inflammation is a protective
response to an inflammatory stimulus and initiates wound-healing
processes. Interleukin-6 (IL6) is an anti-inflammatory cytokine.
The level of C-reactive protein (CRP) in blood rise in the acute
phase of inflammation. Therefore, the level of CRP is a useful
indicator of an acute inflammatory response. The level of
C-reactive protein can be determined by commercially available
ELISA assays. IL6 and CRP have been as clinical markers of
inflammation, see for instance Esme et al. (2011) Effects of
Flurbiprofen on CRP, TNF-, IL6 and Postoperative Pain of
Thoractomy; Int. J. Med. Sci. vol. 8(3): pp 216-221.
[0090] The anti-inflammatory cytokine, Interleukin-6 (IL6) is
assayed as follows: MSD.RTM. Cytokine Assays are used to measure
IL6 in 96-well MULTI-ARRAY.RTM. or MULTISPOT.RTM. plates. The
assays employ a sandwich immunoassay format where capture
antibodies are coated in a single spot, or in a patterned array, on
the bottom of the wells of a MULTIARRAY.RTM. or MULTI-SPOT.RTM.
plate.
[0091] The sample and a solution containing the labeled detection
antibody-anti-IL6 antibody labeled with an electrochemiluminescent
compound, MSD SULFO-TAG.TM. label--are added over the course of one
or more incubation periods. The IL6 in the sample binds to capture
antibody immobilized on the working electrode surface; recruitment
of the labeled detection antibody by bound cytokine completes the
sandwich. The user adds an MSD read buffer that provides the
appropriate chemical environment for electrochemiluminescence and
loads the plate into an MSD SECTOR.RTM. instrument for analysis.
Inside the SECTOR.RTM. instrument, a voltage applied to the plate
electrodes causes the labels bound to the electrode surface to emit
light. The instrument measures intensity of emitted light to
provide a quantitative measure of IL6 present in the sample.
EXAMPLES
Example 1
First in Man Clinical Trial of a Peripherally-Restricted
Non-Narcotic Kappa Receptor Agonist
[0092] This trial was a phase 2 multi-center, double-randomized,
double-blind, placebo-controlled study was conducted to evaluate
the analgesic efficacy and safety of intravenous CR845 dosed
preoperatively and postoperatively in patients undergoing a
laparoscopic hysterectomy. The trial was conducted under an
investigational new drug application (IND) filed with the US Food
and Drug Administration (FDA).
[0093] This phase 2 trial multi-center, double-randomized,
double-blind, placebo-controlled study was conducted in 22 sites in
the United States. All clinical procedures were approved by the
relevant Institutional Review Board (IRB) in compliance with the
applicable laws and regulations of the US. The study was initiated
up to fourteen (14) days preoperatively and the in-hospital period
was approximately twenty-four (24) hours for each patient and
follow up was conducted within seven (7) days of discharge from the
hospital.
[0094] The all-D-tetrapeptide amide, CR845 is a
peripherally-restricted kappa-opioid receptor agonist, in Phase 2
of clinical development for the treatment of acute pain. Thus far,
CR845 has been shown to have analgesic and morphine-sparing effects
in a proof of concept clinical study when administered after
surgery (single intravenous dose) (Menzaghi et al., IASP 2010). In
addition, CR845 appeared to be better tolerated in comparison to
other known kappa agonists, likely due to its limited CNS
penetration.
[0095] The aim of this clinical trial was to evaluate the analgesic
efficacy and safety of intravenous (IV) CR845 dosed preoperatively
and postoperatively in female patients undergoing an elective
laparoscopic hysterectomy. Secondary objectives were: 1. To
evaluate the efficacy of CR845 compared to placebo in reducing pain
following laparoscopic hysterectomy: (a) to determine the time
specific visual analog pain score (VAS) difference, summed pain
intensity differences over all time periods (SPIDs) and pain
relief, etc. and (b) to evaluate the proportion of patents that
were randomized to receive preoperative CR845 and received no
rescue medication postoperatively, compared to those who received
placebo preoperatively and did not receive any rescue medication;
and 2. To evaluate the safety and tolerability of CR845.
[0096] This Phase 2, double-randomized, double-blind,
placebo-controlled, parallel group study was conducted in
approximately 200 female subjects, aged 18 to 65, across 22 US
clinical sites. All subjects were administered a 15-minute IV
infusion of 0.04 mg/kg CR845 or matching placebo before surgery in
a 1:1 ratio. After surgery and upon reaching a pain intensity
baseline level of at least 4 on a 10 cm visual analog scale (VAS),
subjects were also re-randomized in a 1:1 ratio to receive a second
IV infusion of either 0.04 mg/kg of CR845 or placebo. All
doubly-randomized patients were thereby randomized to receive one
of four possible treatment regimens: placebo-placebo,
placebo-CR845, CR845-placebo, or CR845-CR845 (See FIG. 1). Pain
intensity and pain relief scores were assessed up to 24 hours
following the post-surgery infusion. Patients were allowed IV
morphine for rescue at any point during the post-operative period,
if requested.
[0097] The main efficacy endpoints were the total morphine
consumption in the first 24 hours in patients who were
re-randomized in the postoperative period and the efficacy of CR845
in reducing pain intensity including time specific VAS difference;
summed pain intensity differences (SPIDs); area under the curve
(AUC); pain relief; and the proportion of patients that were
randomized to receive preoperative CR845 with no rescue medication
postoperatively. The safety endpoints included the incidence of
adverse events, physical examination, vital signs, 12-lead ECG,
clinical laboratory evaluations, and cumulative fluid balance.
Example 2
Relative Levels of Reduction of Post-Operative Pain (SPIDs)
[0098] FIG. 2 shows the relative levels of reduction of
post-operative pain over the first 24 hours after surgery as
demonstrated by the summed pain intensity difference (SPID) summed
over all of the time points. Patients receiving only placebo showed
the least pain reduction and those receiving CR845 both before and
after surgery showed the greatest reduction in the SPID pain score
(more than twice the reduction over 24 hours as experienced by the
patients receiving only placebo). Patients receiving one dose of
CR845, whether before or after surgery exhibited an intermediate
level of reduction in pain SPID scores (i.e. more relief than seen
in patients receiving only placebo, but less than the relief
experienced by those patients receiving CR845 before surgery and
also after surgery).
Example 2
Relative Levels of Reduction of Post-Operative Pain (PIDs)
[0099] FIG. 3 shows the relative levels of reduction of
post-operative pain over the first 24 hours after surgery as
demonstrated by the pain intensity difference (PID) at each time
point. As shown above for the summed pain intensity difference,
patients receiving only placebo showed the least pain reduction and
those receiving CR845 both before and after surgery showed the
greatest reduction in the SPID pain score (twice the reduction over
24 hours as experienced by the patients receiving only placebo).
Patients receiving one dose of CR845, whether before or after
surgery exhibited an intermediate level of reduction in pain PID
scores (i.e. more relief than seen in patients receiving only
placebo, but less than the relief experienced by those patients
receiving CR845 before surgery and also after surgery).
Example 3
Morphine Self-Administered by the Patients
[0100] FIG. 4 shows the amounts of morphine (in milligrams) self
administered by the patients in each group: placebo-placebo,
placebo-CR845, CR845-placebo, and CR845-CR845 in the interval 2-4
hours, 4-12 hours and 12-24 hours post surgery. Patients receiving
only placebo self-administered the most intrathecally delivered
morphine (mITT), more than doubling the dose self administered from
2-4 hours during each of the 4-12 hour and 12-24 hour periods. By
contrast, those patients receiving two doses of CR845
self-administered the least morphine in each time period.
Example 4
Evaluations of Pain Relief Assessed by Patients
[0101] FIG. 5 shows the evaluations of pain relief as assessed by
the patients themselves. The four patient groups are those
receiving pre- and post-operatively respectively: [0102] (a)
Placebo-Placebo; [0103] (b) CR845-CR845; [0104] (c) Placebo-CR845;
and [0105] (d) CR845-Placebo.
[0106] The Placebo-Placebo group (i.e receiving inactive placebo
instead of the peripherally-restricted kappa opioid receptor
agonist) showed the lowest pain intensity difference (i.e. the
least pain relief) and the group receiving CR845 before and after
surgery showed the highest pain intensity difference (i.e. most
pain relief) as judged by PID score.
Example 4
Global Evaluations of Pain Relief Assessed by Patients
[0107] FIG. 6 shows the overall evaluations of pain relief as
assessed by the patients themselves. The six patient groups are
those receiving pre- and post-operatively respectively: [0108] (a)
Placebo-Placebo; (71 patients) [0109] (b) CR845-CR845; (20
patients) [0110] (c) CR845-Placebo; (19 patients) [0111] (d)
CR845-None; (5 patients) [0112] (e) Placebo-CR845; (71 patients)
and [0113] (f) Placebo-None; (11 patients).
[0114] The highest percentage of patients giving an assessment of
the overall evaluation of the pain relief as "excellent" were in
the CR845 pretreatment groups, i.e. groups (b), (c) and (d). These
data also show that groups pre-treated with CR845 were consistently
evaluated as very good or excellent by the highest percentage of
patients. The above-described clinical data demonstrate that CR845
represents an effective novel therapeutic class useful for
pretreatment of postoperative pain and inflammation.
Example 5
Assay of IL6 in Patient Blood Samples
[0115] The anti-inflammatory cytokine, Interleukin-6 (IL6) is
assayed using the MSD.RTM. Cytokine Assays to measure IL6 in
96-well MULTI-ARRAY.RTM. or MULTISPOT.RTM. plates (Meso Scale
Discovery, Gaithersburg, Md.) according to the manufacturer's
instructions. The assays employ a sandwich immunoassay format where
capture antibodies are coated in a single spot, or in a patterned
array, on the bottom of the wells of a MULTIARRAY.RTM. or
MULTI-SPOT.RTM. plate.
[0116] The serum sample and a solution containing the labeled
detection antibody-anti-IL6 antibody labeled with an
electrochemiluminescent compound, MSD SULFO-TAG.TM. label--are
added over the course of one or more incubation periods. The IL6 in
the sample binds to capture antibody immobilized on the working
electrode surface; recruitment of the labeled detection antibody by
bound cytokine completes the sandwich. The user adds an MSD read
buffer that provides the appropriate chemical environment for
electrochemiluminescence and loads the plate into an MSD
SECTOR.RTM. instrument for analysis. Inside the SECTOR.RTM.
instrument, a voltage applied to the plate electrodes causes the
labels bound to the electrode surface to emit light. The instrument
measures intensity of emitted light to provide a quantitative
measure of IL6 present in the sample.
[0117] Calibrators are run in duplicate to generate a standard
curve. The standard curve is modeled using least squares fitting
algorithms so that signals from samples with known levels of IL6
can be used to calculate the concentration of analyte in the
sample. The assays have a wide dynamic range (3-4 logs) which
allows accurate quantitation in many samples without the need for
dilution. The MSD DISCOVERY WORKBENCH.RTM. analysis software
utilizes a 4-parameter logistic model (or sigmoidal dose-response)
and includes a 1/Y2 weighting function. The weighting function is
important because it provides a better fit of data over a wide
dynamic range, particularly at the low end of the standard
curve.
Example 6
Assay of C-Reactive Protein in Patient Blood Samples
[0118] The Invitrogen Hu CRP kit is a solid phase sandwich Enzyme
Linked-Immuno-Sorbent Assay (ELISA) useful for the determination of
CRP levels in a sample and was used according to the manufacturer's
instructions. Alternatively, CRP levels were determined using the
C-Reactive Protein High Sensitivity Test by Roche Diagnostics
according to the manufacturer's instructions.
[0119] Briefly, a highly purified antibody is coated onto the wells
of the microtiter strips provided. During the first incubation,
standards of known Hu CRP content, controls, and unknown samples
were pipetted into the coated wells. After washing, biotinylated
second antibody was added. After another washing,
Streptavidin-Peroxidase (enzyme) was added. This binds to the
biotinylated antibody to complete the four-member sandwich. After a
third incubation and washing to remove all the unbound enzyme, a
substrate solution was added, which was acted upon by the bound
enzyme to produce color. The intensity of this colored product is
directly proportional to the concentration of Hu CRP present in the
original specimen. Results are shown in FIG. 6. Levels of CRP
appeared to be comparable between patients treated with CR845 pre-
and post-surgically versus placebo. However, it should be noted
that CRP is produced by the liver not by immune cells and so may
not be a good marker for surgically induced inflammation.
Example 7
Thirteen-Plex Assay of Cytokines in Patient Serum Samples
[0120] The Human Cytokine MILLIPLEX MAP assay panel with the
Luminex.RTM. xMAP.RTM. microsphere technology optimized format
(Millipore, St. Charles, Mo.) was used to measure serum
concentrations of a panel of 13 cytokines: IL-1.beta., IL-2, IL-4,
IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, GM-CSF,
IFN.gamma., and TNF.alpha. were quantified in human serum samples
according to the manufacturer's instructions. Samples were serum
samples taken at 1 hour, 8 hours and 24 hours post laparoscopic
surgery in a Phase IIb clinical trial in which subjects were
administered CR845 or placebo as shown in FIGS. 6-14.
[0121] The method uses Luminex.RTM. proprietary techniques to
internally color-code microspheres with two fluorescent dyes.
Assays depend on a hundred distinctly colored microsphere sets,
each of which is coated with a specific capture antibody. The
cytokine in the test sample is captured by the microspheres, and a
biotinylated detection antibody is used as detection agent. The
reaction mixture is then incubated with Streptavidin-PE conjugate,
the reporter molecule, to complete the reaction on the surface of
each microsphere. The microspheres are then passed rapidly through
a laser which excites the internal dyes marking the microsphere
set. A second laser excites PE, the fluorescent dye on the reporter
molecule. A high-speed digital-signal processor is used to identify
each individual microsphere and quantify the result of its bioassay
based on fluorescent reporter signals. Multiple results were thus
obtained from each sample.
[0122] Changes in cytokine levels were detected in most cases (see
FIGS. 6-14), however, changes in cytokine levels that occurred
between the three sampling times or even before 1 hour or after 24
hours post surgery would not have been detected.
Example 8
Adverse Events in Subjects Treated with CR845 or Placebo
[0123] Adverse events (nausea, vomiting and pruritus) occurring in
the first 24 hours post laparoscopic surgery are shown in FIG. 15.
Data are from a Phase IIb clinical trial in which subjects were
administered CR845 or placebo. Generalized pruritus was
distinguished from local pruritus events and shown separately in
FIG. 15. Adverse events were lower in all CR845 treated patient
groups as compared with placebo treated patients.
[0124] The specifications of each of the U.S. patents, allowed and
published patent applications, and the texts of the literature
references cited in this specification are herein incorporated by
reference in their entireties. In the event that any definition or
description contained found in one or more of these references is
in conflict with the corresponding definition or description
herein, then the definition or description disclosed herein is
intended.
[0125] The examples provided herein are for illustration purposes
only and are not intended to limit the scope of the invention, the
full breadth of which will be readily recognized by those of skill
in the art.
* * * * *